Tumour necrosis factor (TNF) alpha affects immune response and airway inflammation, which are characteristics of asthma. Genetic factors may impact TNFalpha levels, and several polymorphisms in the TNF gene cluster on chromosome 6p21 have been associated with TNFalpha production and potential increased risk of asthma. The present paper evaluates the relation between two single nucleotide polymorphisms (SNPs) in the TNF gene cluster and asthma risk. The SNPs investigated here are guanine (G) to adenosine (A) substitutions in the TNFalpha and lymphotoxin alpha (LTalpha) genes. The TNFalpha SNP is at position -308 in the promoter region (TNFalpha-308), while the LTalpha SNP is in the first intron NcoI recognition sequence (LTalpha-NcoI). (For both SNPs the G allele is denoted as 1, and the A allele 2.) We determined TNFalpha-308 and LTalpha-NcoI genotypes in 511 individuals: 236 asthma cases and 275 non-asthmatic controls. Data were analysed by logistic regression of asthma status on the genotypes and potential confounders. TNFalpha-308*2 was positively associated with asthma, and this relation was strengthened when restricting cases to individuals reporting acute asthma: the adjusted odds ratio (OR) comparing carriers of one or two TNFalpha-308*2 alleles versus none was 1.86 (95% confidence interval (CI)=1.03-3.34, P=0.04). Further restricting the subjects to those with a family history of asthma, and those of European-American ancestry strengthened the association even more: adjusted OR=3.16 (95% CI=1.04-9.66; P=0.04). LTalpha-NcoI*1 was weakly associated with asthma, and analysis of both genes suggests that only the TNFalpha-308*2 allele increases risk of asthma.